Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer.
ABSTRACT Transforming growth factor (TGF)-beta is a potent immunosuppressant. Overproduction of TGF-beta by tumor cells may lead to tumor evasion from the host immune surveillance and tumor progression. The present study was conducted to develop a treatment strategy through adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-beta1 and were used as an experimental model. C57BL/6 mice were primed with irradiated TRAMP-C2 cells. CD8+ T cells were isolated from the spleen of primed animals, were expanded ex vivo, and were rendered TGF-beta insensitive by infecting with a retrovirus containing dominant-negative TGF-beta type II receptor. Results of in vitro cytotoxic assay revealed that these CD8+ T cells showed a specific and robust tumor-killing activity against TRAMP-C2 cells but were ineffective against an irrelevant tumor line, B16-F10. To determine the in vivo antitumor activity, recipient mice were challenged with a single injection of TRAMP-C2 cells for a period up to 21 days before adoptive transfer of CD8+ T cells was done. Pulmonary metastasis was either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-beta-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-beta-insensitive CD8+ T cells were able to persist in tumor-bearing hosts but declined in tumor-free animals. These results suggest that adoptive transfer of tumor-reactive TGF-beta-insensitive CD8+ T cells may warrant consideration for cancer therapy.
Article: Modulation of T Cell Tolerance in a Murine Model for Immunotheraphy of Prostatic Adenocarcinoma[show abstract] [hide abstract]
ABSTRACT: The goal of this project is to characterize T cell tolerance to prostate tumor antigens and to identify the role of costimulatory receptors in overcoming this tolerance. Identification of these processes will assist in the development of novel therapeutic approaches for treating prostate cancer. We use the TRAMP model a transgenic mouse line that develops primary prostatic tumors due to expression of the SV4O T antigen (TAg) under the transcriptional control of a prostate-specific promoter. In this final summary we report that subsequent to adoptive transfer of na(ve TAg-specific T cells into TRAMP mice there is rapid expansion and contraction of the tumor-specific T cells followed by accumulation of a population of T cells that persist in the prostate as tolerant and suppressive. Co-transfer of TAg-specific 0D4+ T cells partially rescues the tolerant suppressive phenotype of prostate-tumor-specific T cells although over time tolerance of the CD8+ T cells ensues. In contrast transfer of CD4+ T cells does not reverse tolerance of the previously-tolerized 0D8+ cells. The suppressive nature of these CD8+ T cells was also studied and we present preliminary data on the characterization of these novel suppressor cells. These data demonstrate the critical balance between T cell activation and tolerance and support a mechanism by which tumor growth may induce tolerance and suppressor activity in T cells previously primed to tumor-specific antigens. A greater understanding of how tolerance of these tumor specific T cells can be reversed willcertainly lead to more potent anti-tumor immunotherapies.08/2006;
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ABSTRACT: During the last two decades, several approaches for the activation of the immune system against cancer have been developed. These include rather unselective maneuvers such as the systemic administration of immunostimulatory agents (e.g., interleukin-2) as well as targeted interventions, encompassing highly specific monoclonal antibodies, vaccines and cell-based therapies. Among the latter, adoptive cell transfer (ACT) involves the selection of autologous lymphocytes with antitumor activity, their expansion/activation ex vivo, and their reinfusion into the patient, often in the context of lymphodepleting regimens (to minimize endogenous immunosuppression). Such autologous cells can be isolated from tumor-infiltrating lymphocytes or generated by manipulating circulating lymphocytes for the expression of tumor-specific T-cell receptors. In addition, autologous lymphocytes can be genetically engineered to prolong their in vivo persistence, to boost antitumor responses and/or to minimize side effects. ACT has recently been shown to be associated with a consistent rate of durable regressions in melanoma and renal cell carcinoma patients and holds great promises in several other oncological settings. In this Trial Watch, we will briefly review the scientific rationale behind ACT and discuss the progress of recent clinical trials evaluating the safety and effectiveness of adoptive cell transfer as an anticancer therapy.Oncoimmunology. 05/2012; 1(3):306-315.
Article: Innate Anti-Breast Cancer Activity of -T cells: A Novel Biological and Clinical Approach to the Treatment of Relapsed or Refractory Breast Cancer[show abstract] [hide abstract]
ABSTRACT: We initially identified a specific signaling pathway which inhibits apoptosis in human -T cells. We have exploited this pathway to develop the methodologies allowing the large-scale ex vivo expansion of viable apoptosis-resistant -T cells. Importantly, we have shown that apoptosis-resistant human -T cells retain significant innate (MHC-unrestricted) cytotoxicity against a wide variety of tumor cell lines, including human breast cancer cell lines. In this project, we have focused upon testing the hypothesis that -T cells - by virtue of their innate ability to recognize and kill epithelial-derived malignancies - play an important role in regulating the initial growth or spread of breast cancer in vivo and may also be of therapeutic utility. In this report, we summarize the findings we have made during the course of this project. In both the human pre-clinical work and in the mouse models, we have made the important discovery that -T cells are severely impaired in tumor-bearing hosts (human and mouse) compared to healthy controls - this possibly limiting our ability to use patient-derived (autologous) -T cells for therapy. However, data derived from animal studies clearly show that using -T cells derived from healthy donors (syngeneic or allogeneic) offers a feasible and rationale alternative approach when patient-derived (autologous) -T cells cannot be expanded for use clinically. This represents a significant conceptual advance and is the basis for new studies.02/2009;